The phenotypic characterization of a specimen is a tool that has wide ranging diagnostic applications. For instance, phenotypic characterization of a specimen is needed for tumors in which a tumor's origin cannot be readily identified. These types of tumors are frustrating for pathologists, who are unable to provide a definitive diagnosis, and to oncologists, who thus lack information needed to begin standard-of-care, tissue-directed therapy. Such uncertain results can also add to patient suffering and prevent the efficient use of healthcare resources.
The National Comprehensive Cancer Network's (NCCN) guidelines emphasize the significance of identifying the tissue of origin so that cancer-specific management recommendations can be followed. In a prospective clinical study, Abbruzzese et al. concluded that, for certain challenging cases, “the survival duration of patients in whom the primary tumor was diagnosed was superior to that of patients in whom the primary tumor remained unknown.” See, Abbruzzese et al., 1995, J Clin Oncol. 13: 2094-2103.
In some cases, a battery of tests is performed, yet still fails to definitively identify the primary tumor site. In some especially challenging cases, current pathological techniques, including immunohistochemistry (IHC) and imaging studies, such as x-rays and computed tomography (CT), identify the primary tumor site only 25 percent of the time. Hillen, 2000, Postgrad Med J. 76: 690-693. Clearly, there is a need for a more robust diagnostic solution. This is particularly important, given the availability of newer, more specific, and more effective therapeutic options that target cells of the primary tumor site.
There are a number of tools for determining a phenotypic characterization of a specimen from among a plurality of phenotypic characterizations. One example is immunohistochemistry (IHC), which is a type of assay in which specific antigens are visualized using fluorescent dye or enzyme markers. IHC studies can sometimes identify the primary tumor, even in poorly differentiated metastases. See, for example, Pavlidis et al., 2003, Eur J Cancer. 39: 1990-2005. However, currently available IHC markers do not address the full range of potential tumor types. Another example is cytogenetic methods, which assess chromosomal abnormalities to pinpoint the primary cancer tumor site. While cytogenic methods can provide insights in a number of specific situations, they generally are not in a comprehensive manner. Thus, in the case of cancer, cytogenetic methods are limited because only a few diagnostic chromosomal abnormalities have been identified to date. See, for example, Pavlidis et al., 2003, Eur J Cancer. 39: 1990-2005.
Yet another tool for determining a phenotypic characterization of a specimen from among a plurality of phenotypic characterizations is imaging. CT scans, mammography, magnetic resonance imaging (MRI) and fluorodeoxyglucose (FDG) positron emission tomography (PET) are representative examples of imaging. However, imaging has limitations. For example, in the case of cancer of unknown origin, these various imaging techniques can often be ineffective at determining the origin of the tissue. There are many reasons for the failure of imaging techniques to determine the site of origin of a tumor. These include very small tumor size and confounding structural abnormalities, as well as the limitations of each imaging modality.
Yet another tool for determining a phenotypic characterization of a specimen from among a plurality of phenotypic characterizations is microarray analysis. Although several groups have demonstrated the feasibility of using microarrays to classify uncertain tumors according to tissue of origin, (e.g., Su et al., 2001, Cancer Res. 61: 7388-7393; Ramaswamy, 2002, J Clin Oncol 20: 1932-1941; Giordano et al., 2001, Am J Pathol 159: 1231-1238; Bloom 2004, Am J Pathol 164: 9-16; Buckhaults et al., 2003, Cancer Res 63: 4144-4149; Tothill et al., 2005, Cancer Res 65: 4031-4040; and Ma et al. 2006, Arch Pathol Lab Med 130: 465-473) the application of these varied technologies in the clinical setting has proved a challenge due to the inherent complexity of accurately interrogating and interpreting expression signals from the thousands of distinctive genes that represent the dozen or more tissue types of highest interest. This is the fundamental informatics challenge involving any highly multiplex data. See, for example, Yeang et al., 2001, Bioinformatics 17: S316-S322. While microarrays are theoretically suited to this high degree of multiplexy, no test to date has demonstrated reliability in classifying large numbers of specimens involving the full range of potential tissue types.
The cost to determine a phenotypic characterization of a specimen from among a plurality of phenotypic characterizations can be significant, given that traditional approaches involve multiple technologies that are often run in parallel. For example, in the case of cancer, one study showed that, for certain challenging cases, the primary cancer site was found in only four (7.1 percent) of the 56 cases studied. The average cost of diagnosis was over seventeen thousand dollars. See Tong et al., Poster presented at annual meeting of American Society of Clinical Oncology; Jun. 2-6, 2006; Atlanta, Ga. Another study showed that, in Medicare patients, medical payments averaged $38,000 per patient per year. Tong et al. Poster presented at annual meeting of American Society of Clinical Oncology; Jun. 2-6, 2006; Atlanta, Ga. By rapidly identifying phenotypic characterization of a specimen from among a plurality of phenotypic characterizations, clinicians could potentially apply more appropriate therapies more quickly, potentially enabling improved patient outcomes and a better use of healthcare resources.
When a phenotypic characterization of a specimen from among a plurality of phenotypic characterizations has been made, physicians can provide far better, more focused therapeutic regimens. For instance, in the case of cancer, physicians increasingly have more tissue-specific treatment options. For example, 5-fluorouracil (5-FU)-based therapy was historically the treatment of choice for essentially all gastrointestinal adenocarcinoma tumors, whether they were colonic, pancreatic, or gastroesophageal in origin. However, each of these entities might be treated now with a more individualized approach (e.g., 5-FU/leucovorin with irinotecan or oxaliplatin for colonic, gemcitabine for pancreatic, and perhaps epirubicin, cisplatin, and 5-FU or a taxane for gastroesophageal primaries).
A prevalent problem in the art is the identification of which tissue originated a particular cancer. This is particularly a problem in instances where the cancer is not discovered before it has spread to multiple locations in the body. Of concern in such instances is determining which of the tissues the cancer originated, because such determination will affect the treatment regimen that is prescribed and will improve clinical outcome. For example, if the cancer originated in the bladder, a treatment regimen optimized to treat bladder cancer will be followed, whereas if the cancer originated in the breast, a treatment regimen optimized for breast cancer will be followed.
Identifying the tissue of origin of a poorly-differentiated or undifferentiated tumor at initial presentation can be challenging. Oncology treatment decisions are largely based on the tissue of origin, which makes proper identification vital to selection of the appropriate diagnostic and therapeutic cascades. The National Comprehensive Cancer Network (NCCN) Practice Guidelines recommend that, whenever possible, the tissue of origin should be identified so that the patient may be treated per the NCCN disease-specific guideline. Current diagnostic procedures include a physical examination and full medical history of the patient, laboratory and radiological evaluation, and pathologic assessment. Methods used to characterize a poorly-differentiated or undifferentiated tumor specimen include histologic, immunohistochemical and, when appropriate, electron microscopic evaluations. However, these techniques are limited in their ability to assess the tissue of origin for many poorly-differentiated or undifferentiated tumors. Improved methods are needed to obtain a more definitive diagnosis.
Given the above-background, what are needed in the art are improved systems and methods for phenotypic characterization of a specimen from among a plurality of phenotypic characterizations.
Discussion or citation of a reference herein will not be construed as an admission that such reference is prior art to the present invention.